Infectious diseases are the primary cause of neonatal morbidity and mortality in humans. The World Health Organization has estimated that in 1995 approximately 8 million (6.4% of live-born) infants died within the first year of life from these diseases, including 5 million during the first week of life. Some of the important pathogens involved include Herpes simplex virus (HSV), Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV), Human Cytomegalovirus (HCMV), Group B Streptococcus (GBS), Haemophilus and Chlamydia (Wright, et al., Vaccine (1998) 16:1355-1359; Mulholland, K., Vaccine (1998) 16:1360-1362). Infection with these pathogens can occur in utero, following early rupture of the aminiotic membranes or during birth. In addition, infection may be transmitted during labor by non-sterile techniques, by breast feeding or during the first days of life in a perinatal nursery. To reduce the risk of disease transmission, caesarian sections, prophylactic treatment with antibiotics or maternal antiviral therapy during the last trimester are used where available, together with improved neonatal care. None of these approaches, however, completely eliminates the risk of neonatal infection.
Since the first reports in 1993 (Ulmer, et al., Science (1993) 259:1745-1749), numerous studies have demonstrated that vaccination with DNA represents a very useful tool to induce immunity in people and animals (Donelly, et al., Annu Rev Immunol. (1997) 15:617-648; Babiuk, et al., Adv. Vet. Med. (1999) 41:163-179. In addition to the simplicity of production and delivery, DNA vaccines possess the advantages of attenuated live vaccines with respect to their immunogenicity, and a level of biological safety similar to inactivated vaccines. DNA vaccines represent, therefore, a significant advance in vaccinology. Most studies with DNA vaccines have been performed in mature animals, but within the last three years, several studies have reported succesful immunization of newborns of a variety of species (Butts, et al., Vaccine (1998) 16:1444-1449). As a result, DNA vaccines for rabies, hepatitis B, lymphocytic choriomeningitis-, influenza-, measles-, sendai-, porcine-, bovine herpesvirus-1, and tetanus toxoid are in development (Butts, et al., supra; Le Potier, et al., Vet. Microbiol (1997) 55:75-80; Van Drunen Littel-van den Hurk, et al., Viral Immunology (1999) 12:67-77). These approaches are designed, however, to prevent infections during the first weeks of life. In contrast, fetal immunization might prevent infection in utero, during birth and in the immediate postnatal period and may, therefore, have a significant impact on neonatal survival and the quality of life of infants.
A major factor for preventing an initial infection of the infant is the induction of effective mucosal immunity. This is of particular importance since the majority of infectious agents enter the host via the mucosal surfaces (Staats, et al., In Mucosal Vaccines, 1996 (Kiyono, H., et al., eds.) pp. 17-39). Newborns face an especially high risk of vertical disease transmission during birth and by breast feeding. Recent studies have shown that DNA vaccination via the mucosal surfaces can induce both mucosal and systemic immunity (McCluskie and Davis, Crit. Rev. Immunol. (1999) 19:303-329).
Watts, et al., Nature Med. (1999) 5:427-430 immunized fetal baboons against hepatitis B three times during the last trimester with 5 μg of the recombinant hepatitis B surface antigen protein. Antigen-specific serum antibodies were detectable within 10 days after the second immunization in 75% (5/8) of the immunized fetuses. However, induction of a cell-mediated immune response was not evaluated. Sekhon and Larson, (Nature. Med. (1995) 11:1201-1203) demonstrated that introduction of adenoviral vectors into the amniotic fluid resulted in transgene expression in lung tissue of fetal rats.
The development of effective fetal immunization protocols would provide a valuable approach to reducing the high risk of diseases in newborn children.